Ulcer therapy composition and method of using same



United States Patent 3,155,576 ULCER THERAPY CUR'IPGSETKON AND METHOD GEUSING SAME Paul M. Lish, Hugh D. Bryan, and Neil H. Mercer, Evansville,ind, assignors to Mead Ziohnson dz Corn= parry, Evansviile, End... acorporation of Indiana No Drawing. Filed May 8, 1962, Ser. No. 193,301

0 3 Claims. (Cl. 167-55) US. patent application Serial No. 193,300,filed here with by H. D. Bryan and N. H. Mercer, is concerned with agroup of novel aluminum hydroxide dioctyl sulfosuccinate complexes whichhave pharmaceutical advantages over prior salts of dioctyl sulfosuccinicacid such as sodium dioctyl sulfosuccinate and calciumbis-dioctylsulfosuccinate. The present invention is concerned withpharmaceutical compositions containing the above complexes incombination with antacids, and with the treatment of ulcers.

The present invention involves the discovery that aluminum hydroxidedioctyl sulfosuccinate complexes referred to above reduce gastricsecretion and increase gastric emptying time on contact thereof with theintestinal mucosa. The former property is clearly of value in ulcertherapy. Advantage of the latter can be taken in alleviating ulcersymptoms by co-administration of these substances with antacids since byincreasing gastric emptying time and reducing gastric secretion, theeffectiveness of the antacid dose is enhanced.

More specifically then, this invention involves coadministration of atherapeutic dose of aluminum hydroxide dioctyl suliosuccinate complexand a therapeutic dose of an antacid to a host sufiering from ulcers. Bycoadministration is meant either administration of a unitary compositioncontaining aluminum hydroxide dioctyl sulfosuccinate complex and anantacid or separate, concurrent, or spaced administration of theseactive ingredients so that their periods of pharmacologic elfectivenessoverlap, thereby potentiating or prolonging the efiect of the antacid.Conventional sized doses of antacid and aluminum hydroxide dioctylsulfosuccinate complex are employed. Since the aluminum complex appearsto operate by means of a local contact mechanism on the intestinalmucosa, administration thereof on an empty stomach is sometimesadvantageous. The dose of antacid, or a second dose of antacid alonewhen using a unitary composition of antacid and aluminum hydroxidedioctyl .sulfosuccinate complex, may then follow at an interval of aboutone hour for the desired effect.

The aluminum'hydroxide dioctyl sulfosuccinate complexes are administeredfor anti-ulcer purposes by the oral route in doses ranging from 1.0 to400 mg. per kg. of body weight. Various types of pharmaceutical dosageformulations may be employed, including compressed tablets, chewabletablets, capsules, solutions, suspensions, etc. Compositions in dosageform as anti-secretory medications or antacid potentiators in ulcertherapy contain from to 500 mg. of aluminum hydroxide dioctylsulfosuccinate complex. The aluminum hydroxide dioctyl sulfosuccinatecomplex used in this invention is described in the afore-noted Bryan andMercer application as con taining from about 4.5 to 13.7% aluminum, from4.0 to 7.3% sulfur and up to about 20% water on a weight basis and inthe preferred form from 4.5 to 7 .8% aluminum, from 6.0 to 7.3% sulfurand up to about 10.5% water 'on a weight vbasis. It has been found thatwhen aluminum hydroxide is contacted in solution at pH 3.2 to 4.5 withdioctyl sulfosuccinic acid or a salt thereof in a molecular ratio ofabout 1:1-to 3:1, an aluminum hydroxide "ice dioctyl sulfosuccinatecomplex, as described herein, is formed.

The chewable tablet is the preferred form of antacid compositionscontaining one of the aluminum hydroxide dioctyl sulfosuccinatecomplexes referred to above. Preferred compositions, including liquids,chewable tablets, compressed tablets, and coated tablets, contain from50 to 200 mg. of aluminum hydroxide dioctyl sulfosuccinate complex andfrom 0.2 to 2.0 g. of antacid component per dosage unit. Conventionalantacid ingredients such as calcium carbonate, magnesium carbonate,magnesium trisilicate, sodiumcarbonate, and aluminum hydroxide may beemployed. Examples are provided hereinafter to illustrate compositionsuseful in practicing this invention.

In order to illustrate the etfectiveness of the aluminum hydroxidedioctyl sulfosuccinate complexes as anti-ulcer agents, an experimentinvolving prevention of ulcers in restrained rates is described. Thetest drug in this experiment had a 1:1 ratio on a molecular basis ofaluminum to sulfur and was found on analysis to contain 6.01% Al, 6.67%S, and 4.41% H O. It was prepared from aluminum chloride and sodiumdioctyl sulfosuccinate substantially as described in copendingapplication Serial No. 193,300.

Male or female rats of our colony weighing between 50 and grams weregiven free access to water but restricted from food for 24 hours. Eachrat was lightly anesthetized with ether prior to restraint andadministration of drug. Drugs were administered intraduodenally byhypodermic syringe through a laparotomy incision.

Following drug administration, each rat was placed on a piece ofgalvanized wire screen, 8 inches by 11 inches. The screen was foldedover the rat and stapled around the outer edges. When the rat regainedconsciousness in 5 to 10 minutes, the screen was stapled more closely torestrict movements as much as possible without interfering withrespiration.

Stomachs of the test animals were scored for severity of ulcers sixhours later as follows:

0=negative (no ulcers) l =minimal (one to two very small ulcers)2=average (two or more small or medium ulcers) 4=severe (one or morelarge and several small or medium ulcers) The efiicacy of the drug inpreventing the incidence and/ or severity of ulcers was judged by anumber of factors including the ED values which represent that dose ofdrug, interpolated from log dose-response curves, which reduced theincidence of ulceration to 45 percent or which reduced the severity to amean score of 0.9. By means of this test, the ED value relative toincidence of ulcers for the aluminum hydroxide dioctyl sulfosuccinatetest compound was determined to be 185 mg./ kg. and relative to severitymg./kg. In the same test, atropine sulfate was found to have ED =5mg./kg. as to incidence and ED =about 1.6 as to severity. In other wordsthe aluminum hydroxide complex in doses of 160 to rug/kg. provided thesame anti-ulcer eifect as 1.6 to 5.0 mg/kg. doses or atropine sulfate.

Having now described our invention in a general way, and its applicationin a specific ulcer test in detail, the following examples are providedto more fully illustrate aspects thereof relative to antacidcompositions:

EXAMPLE 1 Antacia' Suspension A suspension containing 50 mg. of aluminumhydroxide dioctyl sulfosuccinate complex and 500 mg. of alu- Ingredient:Amount Aluminum hydroxide-magnesium carbonate compressed gel g 222.2Aluminum hydroxide dioctyl sulfosuccinate complex (Example 1 of Bryanand Mercer Ser. No. 193,300) g 3.33 Sucrose g 200 Methylp-hydroxybenzoate g 1.20 Propyl p-hydroxybenzoate g 0.30 Guar gum(Burtonite V713) g 6.0 Sorbitol, 70% aqueous (Sorbo, Atlas Powder Co.)ml 200 Sodium saccharin g 1.0 Sodium cyclamate g 2.0 Monosodiumglutamate g 1.0 Ethyl vanillin g 1.0 F.D.C. Yellow No. 5 g 0.056Lemon-lime flavor (51.196/A, Firmenich) ml 0.10 Pineapple flavor(51.351/A, Firmenich) ml 0.10 Ethyl alcohol, U.S.P. ml 8.00

Distilled Water, q.s. 1000.00 ml.

Inc., Berkeley Heights, N..T., A1 03,

C02 analyses based on dried mixture).

The sucrose, guar gum, sorbitol, sodium saccharin, sodium cyclamate,monosodium glutamate, and ethyl vanillin are dissolved in 300 ml. ofwater which is first heated to 60 C. The solution is then cooled to 30C. and the color is added thereto. The compressed aluminumhydroxide'nagnesium carbonate gel is then placed in a vessel of suitablesize and the above vehicle is added thereto with mixing. The powderedaluminum hydroxide dioctyl sulfosuccinate complex and the methylp-hydroxybenzoate, propyl p-hydroxybenzoate and the flavors dissolved inthe alcohol are added to the mixture, which is then diluted to 1 l. withdistilled water. The ingredients are all thoroughly dispersed by massingthe suspension through a mechanical homogenizer as the final step.

EXAMPLE 2 Chewable Aiztaczd Tablet An antacid tablet containing 50 mg.of aluminum hydroxide dioctyl sulfosuccinate complex and 400 mg. ofaluminum hydroxide-magnesium carbonate co-dried gel per tablet isprepared as follows. The batch size given is sufficient for 1000tablets.

Step A.-A granulation is prepared from the following ingredients, driedovernight, and crushed so as to pass through a N0. 16 screen.

Ingredient: Amount Aluminum hydroxide-magnesium carbonate co-dried gel g400 Mannitol g 450 Glycine g 150 Sodium saccharin g 1.0 Sodium cyclamateg 10.0 Sodium chloride g 3.0 Gelatin, 30% aqueous solution (dry basis)-g-.. 10.0 Water ml 310 1 Rebels Company, Inc., Berkeley Heights, N.J.,AhOa, 40% M570, 8% CO2, 20% H2O, 8.3%.

Step B.The dried and screened granulation is then thoroughly blendedwith the following ingredients.

4 Ingredient: Amount, g. Aluminum hydroxide dioctyl sulfosuccinatecomplex (Example 1 of Bryan and Mercer,

The blend is then subdivided and pressed into tablets at a weight of1.173 g. in conventional equipment employing a /8 inch round,fiat-faced, beveled edge die.

The following examples are illustrations of compositions of the presentinvention which are designed for immediate release of the aluminumhydroxide dioctyl sulfosuccinate complex with delayed release of theantacid material. These preparations are compression-coated tabletscontaining the aluminum hydroxide dioctyl sulfosuccinate complex in thecoating and the antacid in the core. The tablets are of such a size thatthey cannot pass through the pyloric sphincter and enter the intestinaltract until the coating has been released and the core of antacidmaterial disintegrated. Thus, the tablet is retained in the stomachuntil after the coating containing the aluminum hydroxide dioctylsulfosuccinate complex has been eroded or dissolved and passed into theintestine. The aluminum hydroxide dioctyl sulfosuccinate-containingtablet coat is of such a nature that rapid disintegration thereof isfacilitated, while the antacid core is relatively more resistant todisintegration.

EXAMPLE 3 The following ingredients are employed in preparing a tabletwhich serves as a core for the compressi0ncoated tablet.

Ingredients: Amount, g.

Aluminum hydroxide-mganesium carbonate codried gel) 300 Gelatin 6 Cornstarch 35 Talc 7 Magnesium stearate 2 Total 350 The antacid material ismoistened with the gelatin as a 10% solution in water. The resultingmass is screened, dried, rescreened, and blended with the corn starch,talc, and magnesium stearate. This granulation is then compressed as around standard bi-convex tablet core. The following ingredients are thenformed into a granulation to be employed in applying the compressioncoating.

The aluminum hydroxide dioctyl sulfosuccinate complex is blended withthe lactose and the blend is moistened with a paste prepared from aportion of the corn starch and a small amount of water. The resultingmass is screened, dried, and rescreened and then blended with theremaining corn starch, talc and magnesium stearate. This granulation isthen employed in the final tableting step in which a compression coat isapplied of sufiicient thickness to provide a /2" round standard convexcoated tablet Weighing 750 mg. The batch size given in this example issufficient for 1000 tablets.

EXAMPLE 4 A compression-coated tablet similar to that described inExample 3 is prepared by the procedure of Example 3 employing thefollowing ingredients to prepare the core:

The following materials are substituted in the procedure of Example 3for the preparation of the antacid core. The compression coating isapplied in the same manner and using the ingredients specified in thatexample.

Calcium carbonate precipitated 300 Gelatin 6 Corn starch 35 Talc 7Magnesium stearate 2 Total 350 While several particular embodiments ofthis invention are shown above, it will be understood, of course, thatthe invention is not to be limited thereto, since many modifications maybe made, and it is contemplated, theretore, by the appended claims, tocover any such modifications as fall within the true spirit and scope ofthis invention.

What is claimed is:

1. The process which comprises orally administering to a host sufferingfrom ulcers a therapeutically efiective amount of an antacid and a doseof from 1 to 400 mg. per kilogram of body weight of said host of analuminum hydroxide-dioctyl sulfosuccinate complex containing from about1 to about 3 molecular propor tions of aluminum hydroxide per molecularproportion of dioctyl sulfosuccinate and on a weight basis from 4.5 to13.7 percent aluminum, from 4.0 to 7.3 percent sulfur, and up to about20 percent water, such that the periods of pharmacological eliectivenessof said antacid and said aluminum hydroxide dioctyl sulfosuccinatecomplex overlap.

2. A composition in dosage unit form adapted for oral administrationcontaining from 10 to 500 mg. of an aluminum hydroxide dioctylsulfosuccinate complex comprising from about 1 to about '3 molecularproportions of aluminum hydroxide per molecular proportion of dioctylsulfosuccinate and on a weight basis from 5 to 13.7 percent aluminum,from 4.0 to 7.3 percent sulfur and up to about 20 percent water and atherapeutic amount of a pharmaceutically acceptable antacid.

3. The composition of claim 2 containing to 200 mg. of aluminumhydroxide dioctyl sulfosuccinate com plex and from 0.2 to 2.0 g. of apharmaceutically acceptable antacid.

References Cited in the tile of this patent UNITED STATES PATENTS GoreMar. 31, 1959 Heilig Sept. 8, 1959 OTHER REFERENCES

1. THE PROCESS WHICH COMPRISES ORALLY ADMINISTERING O A HOST SUFFERINGFROM ULCERS A THERAPEUTICALLY EFFECTIVE AMOUNT OF AN ANTACID AND A DOSEOF FROM 1 TO 400 MG. PER KILOGRAM OF BODY WEIGHT OF SAID HOST OF ANALUMINUM HYDROXIDE-DICOTYL SULFOSUCCINATE COMPLEX CONTAINING FROM ABOUT1 TO ABOUT 3 MOLECULAR PROPORTIONS OF ALUMINUM HYDROXIDE PER MOLECULARPROPORTION OF DIOCTYL SULFOSUCCINATE AND ON A WEIGHT BASS FROM 4.5 TO13.7 PERCENT ALUMINUM, FROM 4.0 TO 7.3 PERCENT SULFUR, AND UP TO ABOUT 2PERCENT WATER, SUCH THAT THE PERIODS OF PHARMACOLOGICAL EFFECTIVENESS OFSAID ANTACID AND SAID ALUMINUM HYDROXIDE DIOCTYL SULFOSUCCINATE COMPLEXOVERLAP.